Effects of rolipram and zaprinast on learning and memory in the Morris water maze and radial arm maze tests in naive mice.

Inhibition of phosphodiesterase 5 (PDE) improved recognition memory and counteracted spatial learning impairment induced by nitric oxide synthase (NOS) inhibition in recent studies. Aim of this study was to investigate effects of rolipram, a PDE4 inhibitor and zaprinast, a PDE5 inhibitor, on learning and memory in Morris water maze (MWM) and radial arm maze (RAM) tests in naive mice. Male Balb-c mice were treated subchronically with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) for 6 days in the MWM test and acutely before the retention trial of radial arm maze test. Rolipram (0.05 and 0.1 mg/kg) significantly decreased escape latency between 2(nd) and 5(th) sessions, while zaprinast (10 mg/kg) significantly decreased escape latency only in 2(nd) session. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly increased time spent in escape platform's quadrant in probe trial of MWM test; only rolipram decreased mean distance to platform, while zaprinast had no effect on mean distance to platform. Zaprinast (3 and 10 mg/kg) significantly decreased number of errors compared to control group, while rolipram (0.05 and 0.1mg/kg) had no effect on number of errors in retention trial of RAM test. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly decreased time spent to complete retention trial (latency) compared to control group. Our study revealed that both zaprinast and rolipram enhanced spatial memory in MWM, while zaprinast seems to have more memory enhancing effects compared to rolipram in radial arm maze test.

Effects of olanzapine and clozapine on radial maze performance in naive and MK-801-treated mice.

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25 mg/kg, i.p.) and clozapine (0.5 and 1 mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2 mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.

Venous thromboembolism risk and thromboprophylaxis among hospitalized patients: data from the Turkish arm of the ENDORSE study.

OBJECTIVES: To evaluate venous thromboembolism (VTE) risk and use of thromboprophylaxis in the acute care hospital setting. METHODS: A total of 1701 patients hospitalized for acute or exacerbated chronic medical illnesses or elective major surgery at 11 different hospitals across Turkey were included in the study. Patients at risk and VTE prophylaxis application were retrospectively identified based on medical charts. RESULTS: According to the American College of Chest Physicians (ACCP) criteria, overall 35.6% (606 of 1701) of the patients were identified to be at VTE risk. Venous thromboembolism-risk was observed in 64.9% of surgical and 23.8% of medical patients, the latter being lower than global Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study results; while prophylaxis was prescribed in 39.0% and 38.5% of them, respectively. Contraindication to anticoagulant prophylaxis was observed in 8.7% of medical and 8.8% of surgical patients. CONCLUSIONS: VTE remains a risk factor among patients hospitalized across Turkey, since identification as well as prophylaxis of patients at VTE risk seems to be neglected.

Effects of long-term treatment with fluoxetine and venlafaxine on rat isolated vas deferens.

Antidepressant therapy is considered as one of the factors leading to male infertility. In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1-64 Hz), noradrenaline (10(-8) to 10(-4) M), serotonin (10(-8) to 10(-4) M), adenosine 5'-triphosphate [ATP (10(-8) to 10(-4) M)] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips. Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions. In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.

Effects of diabetes and elevated glucose on nitrergic relaxations in the isolated duodenum of the rat.

Nitrergic relaxations of the isolated duodenum, induced by streptozotocin, were investigated in the experimental 8-week diabetes rat model. The effects of elevated glucose were also examined in the incubated duodenal muscles (in Krebs-Henseleit solution containing 44 mM glucose for 6 h) taken from nondiabetic rats. The relaxations induced by electrical field stimulation (EFS) and nicotine were significantly reduced in diabetic rats compared with control rats. Incubating of duodenal tissues in medium containing elevated glucose revealed significantly impaired relaxations to EFS and nicotine compared to responses obtained after normal glucose incubation. However, the relaxant responses to sodium nitroprusside and papaverine were similar in all groups. Incubating in hyperosmolar solutions containing sucrose, the relaxant responses were not affected. In conclusion, impairment of NO-mediated relaxations in diabetes may be related to hyperglycemia. The alterations caused by elevated glucose are not due to a hyperosmotic effect because the same concentration of sucrose had no effect on the relaxations.

Secondhand tobacco smoke impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle: improvement with chronic oral administration of L-arginine.

The first goal of this study was to examine the effect of secondhand smoking on neurogenic, endothelium- and cGMP-dependent relaxant responses of rabbit corpus cavernosum smooth muscle. Our second goal was to determine whether such an effect can be prevented by oral administration of L-arginine. Male New Zealand rabbits were divided into control, chronic passive cigarette smoking and L-arginine treatment groups. Relaxant or contractile responses in isolated corpus cavernosum smooth muscle strips were determined by using in vitro muscle technique. There was no significant difference in the relaxant response of the strips to papaverine, sodium nitroprusside and contractile response to KCl among the groups. Relaxant responses to acetylcholine and electrical field stimulation and contractile response to phenylephrine were significantly decreased in the strips of the smoking group than that of the control group. The impaired relaxations of strips were markedly improved by treatment of L-arginine, but the contractile responses to phenylephrine were not affected. These data indicate that secondhand smoking may impair both neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle, and may contribute to the etiology of impotence. Chronic dietary supplementation with L-arginine offsets the impairment of neurogenic and endothelial relaxation. Therefore, we suggest that secondhand smoking exposure to cigarette produces selective impairment of neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle via a mechanism related to the decreased production and/or availability of nitric oxide.

Impaired esophageal reactivity in adriamycin-induced rat esophageal atresia: an in vitro study.

PURPOSE: The aim of this study was to investigate the reactivity of lower esophageal smooth muscle in the Adriamycin-induced esophageal atresia (EA) rat model. METHODS: The fetuses were divided into 3 groups. The control group was exposed to saline. The second group comprised fetuses that were exposed to Adriamycin but in whom EA did not develop. The third group comprised of fetuses that were exposed to Adriamycin and EA was observed. The reactivity of distal esophageal strips was studied in organ chambers. RESULTS: The tension was similar in all groups precontracted with carbachol for the study of relaxation to serotonin. Relaxation of lower esophageal strips to serotonin was comparably unaffected in the control and Adriamycin-no EA groups, whereas it was significantly inhibited in the EA group with decreased E(max) and pD(2) values. Contractile responses of esophageal smooth muscle to carbachol or 80 mmol/L KCl and relaxant responses to papaverine were similar in all groups. No change in agonist potency was observed among the groups. CONCLUSIONS: Our study showed impairment of serotonin-receptor-mediated relaxation; but not of cholinoceptor-mediated contraction of the lower esophageal smooth muscle in the EA. Thus, impaired relaxant responses may be, at least in part, a contributing factor in the esophageal dismotility seen in EA.

Chronic ethanol consumption impairs adrenoceptor- and purinoceptor-mediated relaxations of isolated rat detrusor smooth muscle.

OBJECTIVE: To investigate the effects of chronic ethanol consumption on the reactivity of detrusor smooth muscle. MATERIALS AND METHODS: Eight male rats received ethanol (7.2% v/v) in a modified liquid diet for 4 weeks. Two control groups were assessed; eight rats in one group were fed sucrose and received a liquid diet, and 12 rats in the second group received standard rat chow and water for 4 weeks. The reactivity of detrusor smooth muscle strips from ethanol-fed animals and control animals was evaluated in organ chambers. RESULTS: The relaxation response elicited by isoprenaline or adenosine was unaffected in the both control groups while it was significantly inhibited, with decreased maximum responses and pD2 values, in the ethanol-fed group. Contractile responses of detrusor smooth muscle to carbachol or 80 mmol/L KCl and relaxant responses to papaverine were similar in the control groups and the ethanol-fed group. There was no change in agonist potency among the groups. CONCLUSION: Chronic ethanol consumption impairs beta-adrenoceptor- and purinoceptor-mediated relaxation but not cholinoceptor-mediated contraction of the rat detrusor smooth muscle. Thus, it appears that different regulatory mechanisms are involved in ethanol-induced alterations in beta-adrenergic, purinergic and muscarinic receptors in detrusor strip.

Impaired neurogenic and endothelium-dependent relaxant responses of corpus cavernosum smooth muscle from hyperthyroid rabbits.

We investigated the effect of hyperthyroidism on the responsiveness of the rabbit corpus cavernosum smooth muscle. In male albino rabbits, hyperthyroidism was established by oral feeding of L-thyroxine at increasing dosages (150-450 microg/kg) over an 8-week period. This treatment produced a stable hyperthyroid state as indicated by the increased serum T4 levels. The reactivity of corpus cavernosum tissue from hyperthyroid animals and euthyroid control animals was studied in organ chambers. Hyperthyroidism caused impaired neurogenic and endothelium-dependent relaxant responses with decreased Emax and pD2 values. However, hyperthyroidism had no effect on both phenylephrine- and KCl-induced contractile responses and sodium nitroprusside- and papaverine-induced endothelium-independent relaxant responses, and there was no change in agonist potency. These data indicate that hyperthyroidism may impair both neurogenic and endothelium-dependent relaxation of corporal smooth muscle, and may contribute to the etiology of impotence.

Antinociception induced by verapamil and chloramphenicol in mice.

The analgesic effects of verapamil, a calcium channel blocker, and chloramphenicol, a phenicolated antibiotic, were compared using the test of acetic-acid-induced writhing and the hot-plate test in mice. The results suggest that both drugs have antinociceptive properties comparable to salicylate analgesia. No significant difference was found between verapamil- and chloramphenicol-induced analgesia (p < 0.05).

The Effects of Daflon on Pelvic Pain in Women with Taylor Syndrome

The syndrome of chronic pelvic pain without an obvious pathology has been described as pelvic congestion (Taylor) syndrome. It is frequently associated with continuous bilateral lower abdominal pain and dyspareunia. Pelvic examination reveals tenderness without induration or masses. Although their importance in the pathophysiology of pain is uncertain, prominent enlarged broad ligament veins are observed at laparoscopy. We evaluated the effects of daflon, a venomimetic agent that regulates the circulatory tonus of the venous system, on pelvic pain and investigated the role of enlarged veins in the pathophysiology of Taylor syndrome. Ten women (age 28-35 yrs) with chronic pelvic pain were diagnosed with the syndrome at laparoscopy. They all had prominent broad ligament and ovarian veins without other pathologies such as endometriosis to explain the etiology of pelvic pain. Five women were randomized in a double-blind fashion to receive daflon 500 mg twice/day for 4 months, and five a vitamin pill placebo; they were crossed over for another 4 months. They scored the frequency and severity of lower abdominal pain and dyspareunia on a scale from 0 to 6, and the results were compared with pretreatment values. At the end of the fourth month the frequency and severity of pelvic symptoms began to decrease with daflon compared with pretreatment and placebo. The mean scores were significantly less at the end of 4 months (9.3 ± 1.1 vs 4.2 ± 1.4, respectively, p <0.05). Based on our preliminary results, we conclude that venous dysfunction and stasis may be pathophysiologic components of pelvic pain in women with Taylor syndrome. Pharmacologic enhancement of venous tonus may restore pelvic circulation and relieve pelvic symptomatology.

The Sensitivity of Low-Dose Oral Contraceptives in Differentiating Endometriosis in Patients with Pelvic Pain

We evaluated the effects of low-dose oral contraceptive (Desolett) in the management of pelvic pain, and its sensitivity in differentiating organic disorders such as endometriosis, in 96 women who were followed for at least 4 to 6 months. The 67 who still complained of pelvic pain with no improvement in severity, or who reported increase in symptoms after 4 to 6 months were examined by laparoscopy. All patients underwent laparoscopy in the follicular phase, under general anesthesia with the three-puncture technique. Fifty-six women (83.6%) were diagnosed as having endometriosis, 19 stage 1, 31 stage 2, and 6 stage 3 disease (American Fertility Society classification). Six (9%) had moderate to severe pelvic adhesions (2 Fitz-Hugh-Curtis syndrome) with no endometriotic implants. One (1.5%) had Taylor syndrome, and the others (6%) were free of disease. Unresponsiveness to low-dose oral contraceptives at the end of 4 to 6 months was highly sensitive and predictive of organic pelvic disorders such as endometriosis as the cause of pelvic pain. Therefore, we conclude that this therapy is effective in evaluating and treating women with obscure findings for particular disorders. In addition to managing mild to moderate endometriosis, it is effective in reducing the severity of midline pelvic pain of uterine origin, which may be of further benefit in pelvic pain of obscure etiology. Finally, a trial of oral contraceptives may be used as initial screening in women with chronic pelvic pain to reduce the number of unnecessary diagnostic and surgical interventions.

Effectiveness and Long-Term Safety of Prolonged Gosereline and Tibolone in Women with Endometriosis

Gonadotropin-releasing hormone (GnRH) agonists are widely administered to treat endometriosis, but generally are not prescribed for more than 6 months since they are associated with vasomotor symptoms and bone loss. A GnRH agonist and steroid add-back therapy can be given for longer times without flare-up or significant hypoestrogenic symptoms. We examined the efficacy and safety of a weak estrogenic steroid, OD14, with prolonged goserelin treatment in seven regularly menstruating women (age 26-33 yrs) with laparoscopically diagnosed, symptomatic endometriosis. The women received goserelin 3.65 mg subcutaneously/month and 2.5 mg OD14 2.5 mg/day beginning in the fourth cycle for 18 to 20 months. The frequency and severity of hot flushes, sweating, irritability, loss of libido, nervousness, and sleeplessness were scored by the women on a scale of 0 to 6 and compared. Samples of blood and urine were obtained to measure serum estradiol (E2) levels, lipids, and urinary calcium:creatinine (Ca:Cr) ratios at the start of treatment and monthly thereafter. The vasomotor scores, serum E2 levels, and urine Ca:Cr ratios were consistent with the hypoestrogenism induced by goserelin (24.2 ± 3.1, 18.5 ± 7.2 pg/ml, and 0.063 ± 0.008, respectively). The decreases in vasomotor scoring with regard to hot flushing, sweating, and urinary Ca:Cr ratios were significant after adding OD14 (14.8 ± 2.2, 0.031 ± 0.005, p <0.05), whereas E2 levels remained below 40 pg/ml (23.1 ± 8.2 pg/ml, p >0.05) throughout therapy. The increased low-density:high-density lipoprotein ratio with goserelin improved with OD14, remaining at the lower limit of normal. Thus, OD14 add-back to GnRH agonist therapy enabled us to extend medical therapy of endometriosis longer than 6 months, preventing hypoestrogenic side effects, and with adequate suppression endometriosis symptoms.

In the hippocampus in vivo, nitric oxide does not appear to function as an endogenous antiepileptic agent.

Using a reverberatory epilepiform discharge of hippocampal-parahippocampal circuits termed "maximal dentate activation", this study investigated whether the local release of nitric oxide within these circuits functions as an antiepileptic agent. Two nitric oxide synthase inhibitors (L-nitro-arginine methyl ester and 7-nitro-indazole) and a guanylate cyclase inhibitor (methylene blue) were tested, and none had a significant effect on the time to onset or duration of maximal dentate activation. A membrane-permeable analogue of cyclic guanosine monophosphate (cGMP), 8-bromo-cGMP, caused an increase in the time to onset and a decrease in the duration of maximal dentate activation. The number of neurons expressing NADPH diaphorase activity (a marker for nitric oxide synthase) was also examined after repeated elicitation of maximal dentate activation. After 18 seizures there was a significant, but transient, decrease in the number of hilar/subgranular neurons that were NADPH diaphorase-positive. The decrease was only seen at 1 h after the last seizure. There was no induction of NADPH diaphorase activity. These results are not consistent with the hypothesis that, in hippocampal-parahippocampal circuits in vivo, nitric oxide is released in response to neuronal activity and then acts to terminate the neuronal activity.

Effects of vitamin C intake on whole blood plasma, leucocyte and urine ascorbic acid and urine oxalic acid levels.

Fifty volunteers among the students of the Faculty of Pharmacy at Ankara and Gazi Universities were taken 2 grams of Vitamin C per day at regular time intervals for two months. Blood and urine samples were collected in the beginning, one month and 2 months after vitamin administration. The whole blood, plasma and leucocyte ascorbic acid levels were increased after one and 2 months treatment. The urine ascorbic acid were also increased significantly. Urine oxalic acid were not elevated after vitamin C intake.

Ascorbic acid effect on some lipid fractions in human beings.

A group of 50 volunteers of our Faculty students have taken Vitamin C 2 g per day at regular time intervals for 2 months. Blood samples were taken in the beginning, one month and 2 months after vitamin administration. Cholesterol, HDL-cholesterol, lipoprotein and triglyceride concentrations were determined. Cholesterol concentrations were decreased significantly at the end of treatment. Triglyceride concentrations were decreased also in first and second month. HDL-cholesterol were rised significantly and alpha and beta fractions of lipoprotein were increased.